Features of Cytokine Storm Identified by Distinguishing Clinical Manifestations in COVID-19
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PERSPECTIVE
published: 24 May 2021
doi: 10.3389/fpubh.2021.671788
Features of Cytokine Storm Identified
by Distinguishing Clinical
Manifestations in COVID-19
Wei-Xi Shen 1,2*, Rong-Cheng Luo 1,2 , Jing-Quan Wang 3 and Zhe-Sheng Chen 3*
1
Shenzhen Hospital, Southern Medical University, Shenzhen, China, 2 Shenzhen Tianyou Medical Institute, Shenzhen, China,
3
College of Pharmacy and Health Science, St. John’s University, New York, NY, United States
Coronavirus disease 2019 (COVID-19) is caused by a new coronavirus, namely severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently spreading
all over the world. In this paper, we developed a practical model for identifying the
features of cytokine storm, which is common in acute infectious diseases and harmful
manifestation of COVID-19, by distinguishing major and minor clinical events. This model
is particularly suitable for identifying febrile and infectious diseases like COVID-19. Based
on this model, features of cytokine storm and pathogenesis of COVID-19 have been
Edited by: proposed to be a consequence of the disequilibrated cytokine network resulting from
Jean Challacombe,
Twist Bioscience, United States
increased biological activity of transforming growth factor-β (TGF-β), which induces
Reviewed by:
certain clinical manifestations such as fatigue, fever, dry cough, pneumonia, abatement
Shanzhi Wang, and losing of olfactory, and taste senses in some patients. Research and clarification of
University of Arkansas at Little Rock,
the pathogenesis of COVID-19 will contribute to precision treatment. Various anti-TGF-β
United States
Pranjal Sarma, therapies may be explored as potential COVID-19 treatment. This novel model will be
University of Cincinnati, United States helpful in reducing the widespread mortality of COVID-19.
Guangfu Li,
University of Missouri, United States Keywords: coronavirus disease 2019 (COVID-19), clinical manifestation, cytokine storm, pathogenesis,
transforming growth factor-β (TGF-β)
*Correspondence:
Wei-Xi Shen
shenweixi2006@126.com
Zhe-Sheng Chen INTRODUCTION
chenz@stjohns.edu
The coronavirus disease 2019 (COVID-19) pandemic is currently spreading worldwide and
Specialty section: contributing to widespread mortality. There is an urgent need to clarify the pathogenic mechanism
This article was submitted to underlying the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In
Infectious Diseases - Surveillance, response, on the basis of our comprehensive clinical experience, profound understanding of
Prevention and Treatment, cytokine network, and the recognition of the comparative research between Chinese medicine and
a section of the journal
modern medicine over the past years (1–4), we developed a practical diagnostic model to judge
Frontiers in Public Health
and identify the features of cytokine storm of acute infectious diseases by distinguishing the clinical
Received: 26 February 2021 manifestations of patients. The features of cytokine storm elicited by COVID-19 were clarified as a
Accepted: 27 April 2021
typical application of this model.
Published: 24 May 2021
Citation:
Shen W-X, Luo R-C, Wang J-Q and
CLINICAL MANIFESTATIONS OF COVID-19
Chen Z-S (2021) Features of Cytokine
Storm Identified by Distinguishing The main symptoms of COVID-19 are fever, fatigue, dry cough, abatement and losing of olfactory
Clinical Manifestations in COVID-19. and taste senses. Patients with severe symptoms may also experience dyspnea, hypoxemia, shock,
Front. Public Health 9:671788. and multiple organ failure (5, 6). In the early stage of COVID-19, patients usually have unchanged
doi: 10.3389/fpubh.2021.671788 or decreased number of white blood and decreased number of lymphocytes, with multiple small
Frontiers in Public Health | www.frontiersin.org 1 May 2021 | Volume 9 | Article 671788
Shen et al. Cytokine Storm and COVID-19 Manifestations
patch shadows and interstitial lesions on lung CT images. manifestations of the disease. This is because at this time the
Autopsies on patients with COVID-19 show obvious manifestations are caused by the genuine cytokine storm of
inflammation of lungs accompanied with large amount of the primary disease without other noisy factors. The clinical
mucus (7). manifestations are much more complicated after the disease has
The clinical manifestations of COVID-19 can be divided triggered a series of secondary pathological processes. Moreover,
into four categories. (1) The major manifestation: A major the basis and key to identify cytokine storm feature still need
symptom of COVID-19 is fatigue, with the degree of fatigue to have a profound understanding of cytokine network, and
being associated with the clinical type of COVID-19. (2) master the biological activities of various cytokines and current
Minor manifestations: fever, dry cough, abatement and losing knowledge of cytokines progress.
of olfactory and taste senses, interstitial lung changes, and
lymphopenia. The major and minor manifestations are directly
caused by the disequilibrated cytokines of COVID-19. (3) FEATURES OF CYTOKINE STORM AND
The manifestations due to secondary pathogenic processes: PATHOGENESIS OF COVID-19
sputum and chest distress caused by secondary lung bacterial
infection. Patients with severe symptoms may display respiratory Abnormal expression and dysfunction of cytokines in diseases
failure, shock, and multiple organ failure, as well as blood can lead to a certain disequilibrated cytokine network and elicit
pressure reduction, poor peripheral perfusion, and so on. corresponding pathogenic changes and manifestations (9–11).
(4) The manifestations of comorbidities: comorbidities such The disequilibrated cytokine network status of diseases can be
as diabetes, hypertension, and coronary heart disease may divided into three levels: mild, ordinary, and critical. Commonly,
be enhanced by the infection and progression of COVID- a critical level of disequilibrated cytokine network status is
19 (8). The mixed manifestations make the identification known as cytokine storm, which means an excessive number
of cytokine storm and actual pathogenesis of COVID-19 and quantity of cytokines are released. Cytokine storm can
extremely difficult. lead to the production of a number of biological mediators
that interfere with normal cell function and cause systematic
alterations, causing inflammation in the area of the body being
A PRACTICAL DIAGNOSTIC MODEL TO flooded, which can be fatal.
IDENTIFY CYTOKINES AND CLINICAL Increasing evidence has shown that a number of cytokines,
MANIFESTATIONS including interleukins (IL-1, IL-6, IL-8), tumor necrosis factor
(TNF), a-nd interferon (IFN) displayed significant changes in
The understanding and recognition of diseases are achieved COVID-19 patients (12). However, the features of cytokine storm
based on the systematic investigation of etiology, pathogenesis, of COVID-19 have not been well-identified due to the complexity
pathogenic process, clinical manifestations, treatment, and of the cytokine network. And few studies have focused on the
rehabilitation. The dysfunction of cytokine network and clinical change and role of transforming growth factor-β (TGF-β) during
manifestations of diseases are closely associated with each COVID-19 infection.
other and have a causal relationship. Different pathogenesis Following the above model, we proposed that cytokine storm
and disequilibrated cytokine network status will yield different in COVID-19 was a consequence of disequilibrated cytokine
pathological processes, and in return, different manifestations. network resulting from increased biological activity of TGF-
Cytokines are a group of polypeptides functioning as first β. SARS-CoV-2 viruses proliferate and reproduce in their
messenger molecules, and play key roles during the occurrence, target cells, inducing abnormal stress and immune responses
development, and evolution of diseases. Clinical manifestations of the body. This process disturbs the normal expression
of diseases depend on the leading cytokines which play dominant and functional regulation mechanisms of cytokines, finally
roles in the disequilibrated cytokine network status. resulting in disequilibrated cytokine network dominated by TGF-
Based on the causal relationship between cytokines and β and its synergetic factors. TGF-β binds to its corresponding
manifestations, we developed a practical diagnostic model to receptors and triggers a series of cascade biochemical reactions,
identify the features of cytokine storm as a result of acute pathological processes, and clinical manifestations (Figure 1).
infectious diseases. This model includes the following diagnostic TGF-β is a cytokine superfamily and has a broad spectrum of
procedures: (1) observing and distinguishing the patient’s biological activities in the body. As an endogenous pyrogen,
comprehensive clinical manifestations; (2) differentiating the TGF-β can cause fever, but its pyrogenicity is relatively weak
major, minor, secondary, and other manifestations; (3) judging and usually only results in low fever (13). Fatigue is a
the leading cytokines that display the dominant roles of the typical symptom of COVID-19, potentially due to mitochondrial
disequilibrated cytokine network and eliciting the manifestations dysfunction and decline Na+ -K+ -ATPase activity (14, 15). Dry
of diseases, and; (4) identifying the features of cytokine storm of cough and interstitial lung change are also caused by increased
the diseases. Following this model, the pathogenesis and features TGF-β, which is a fibroblast growth factor and has been
of cytokine storm of COVID-19 infection was elucidated in shown to induce interstitial lung change. TGF-β promotes the
the following. secretion of bronchial mucus cells, induces large amounts of
Thus, it can be seen that when we judge and identify the thick mucus and pulmonary sputum embolism in the lungs,
cytokine storm, we are particularly focusing on the initial clinical which hinders normal breathing, and may lead to critical
Frontiers in Public Health | www.frontiersin.org 2 May 2021 | Volume 9 | Article 671788Shen et al. Cytokine Storm and COVID-19 Manifestations
FIGURE 1 | The pathogenic mechanism of COVID-19 manifestations.
complications, such as serious infections and shock. In addition, are consistent with the corresponding levels of mild, moderate,
TGF-β is a strong immunosuppressive factor in the body, and critical cytokine storm, respectively. The different clinical
significantly suppressing immune function and delaying recovery types might be due to different cytokine storm and different
(16). Furthermore, TGF-β can inhibit the proliferation and immune response of the body. A basic feature of COVID-19
differentiation of lymphocytes (17), reducing the number of cytokine storm is an abnormally increased TGF-β activity.
peripheral blood lymphocytes. TGF-β has negative impacts on However, due to the differences between individuals, different
olfactory and gustatory receptor neurons and neurogenesis by COVID-19 patients and even the same patient at different stages
inhibiting progenitor cell proliferation and differentiation, elicits may show inconsistent pathogenesis and clinical manifestations.
the abatement and losing of olfactory and gustatory sense in some In clinical practice, physicians should strive to make a timely
patients (18–20). Overall, the clinical manifestations of COVID- identification based on such clinical manifestations. For example,
19 are highly consistent with increased TGF-β activity, which when the disease is mainly characterized by obvious fatigue and
is the basic evidence supporting TGF-β as the main player of low fever, TGF-β might be the dominant factor. In contrast,
cytokine storm resulting from SARS-CoV-2 infection. when the main manifestation is hyperpyrexia, IL-1, and TNF-α
might be increased and more likely to be the dominant factors.
HETEROGENEITY AND DISCREPANCY OF By comparing the clinical manifestations of COVID-19 and
COVID-19 CYTOKINE STORM SARS, we see significant difference in cytokine storm. The clinical
manifestations of SARS include high fever, cough, dyspnea, and
COVID-19 patients can be divided into three types: fatigue. The major symptom of high fever of SARS suggests that
asymptomatic/mild, ordinary, or critical types (Figure 2), which the leading factors of cytokine storm is related to the increased
Frontiers in Public Health | www.frontiersin.org 3 May 2021 | Volume 9 | Article 671788Shen et al. Cytokine Storm and COVID-19 Manifestations
FIGURE 2 | The overall pathogenic process and cytokine storm of COVID-19.
activity of inflammatory cytokines such as IL-1 and TNF-α. Currently, there is no antiviral agent that works against
However, the major symptoms of COVID-19 are fatigue and SARS-CoV-2, although there is something like Remdesvir
relatively mild fever indicate that it is highly associated with and hydroxychloroquine. Hydroxychloroquine has shown some
increased activity of TGF-β. effects when administered with azithromycin in some studies,
but more recent study conclude that hydroxychloroquine alone
SIGNIFICANCE OF CLARIFYING THE is not effective for the treatment of COVID-19 and that the
FEATURE OF CYTOKINE STORM combination of hydroxychloroquine and azithromycin increases
the risk of mortality (21, 22). Although the US FDA granted
Clarifying the feature of cytokine storm of COVID-19 is the emergency use of Remdesivir in April, 2020, and a recent
helpful for selecting precise treatment and improving efficacy. report by Beigel et al. concluded that Remdesivir was superior
Frontiers in Public Health | www.frontiersin.org 4 May 2021 | Volume 9 | Article 671788Shen et al. Cytokine Storm and COVID-19 Manifestations
to placebo in shortening the time to recovery in patients who insufficient, however, to comprehensively understand and
were hospitalized with COVID-19, Remdesivir does not seem master the holistic dysfunctional changes of the whole
to reduce COVID-19 mortality so far (23). Thus, aside from body. The changing regulation and dysfunctional status
symptomatic and supportive care, prevention and treatment of the cytokine network make it difficult to determine
of complications, various effective anti-TGF-β therapies should and identify only by detecting the content changes of a
be explored, including cytokine therapy, cytokine neutralizing lot of or even all the cytokines. This study proposes a
antibodies, glucocorticoids, Chinese herbs, drugs that inhibit model and reveals the relationship between cytokines and
TGF-β activity, and interfere with TGF-β signal transduction. clinical manifestations. The practical diagnostic model we
Previous studies have supported that targeting TGF-β activity used in identifying the features of cytokine storm could
is effective against COVID-19. Some traditional Chinese drugs, guide diagnosis and treatment of COVID-19 and other
such as Suctellaria baicalensis and Utrica dioica (24), as well as infectious diseases.
ginseng, have an inhibitory effect on TGF-β activity and can
be used to alleviated symptoms of COVID-19 (25). Kaempferol, DATA AVAILABILITY STATEMENT
which can inhibit the secretion of mucus from goblet cells,
is beneficial for the prevention and treatment of mucus The original contributions presented in the
hypersecretion of the lungs (26, 27). Diterpene phenol extract study are included in the article/supplementary
of Rosmarinus officinalis has been reported to inhibit TGF-β in material, further inquiries can be directed to the
rats (28). N-acetylcysteine (NAC) was used for the prevention corresponding author/s.
and treatment of COVID-19. NAC has mucolytic (anti-mucous)
effects. In addition, NAC can inactivate TGF-β and prevent its
binding to its receptor (29). Recently, we adopted a strategic AUTHOR CONTRIBUTIONS
approach to repurpose the use of clinically approved drugs
against SARS-CoV-2. We uncovered that NAC is able to interrupt W-XS, R-CL, and Z-SC conceptualized the manuscript. W-XS
the spike protein of the virus and therefore, stop the virus from wrote the manuscript. R-CL, J-QW, and Z-SC edited the
entering into the host cells. Our results support current clinical manuscript. All authors read and approved the final version
trials of NAC for treating severe COVID-19 patients (30). for submission.
DISCUSSION FUNDING
Great progress has been made in recognizing and detecting This work was supported by Sanming Project of Medicine in
the substantial and structural changes of diseases. This is Shenzhen (No. SZSM201612023).
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